Syringes for prefilled and fill-at-use mixing and drug delivery

ABSTRACT

Mixing syringes including a valve mechanism are configured and configurable to enable one or more substances to be prefilled into the syringe. The valve mechanism may be an aspect of a distal seal assembly. Actuation of the valve mechanism permits opening of a fluid passage for the mixing of one or more substances, and the resulting mixed substance can be delivered by the syringe, for example, for administration of a pharmaceutical to a subject.

RELATED APPLICATIONS

This application claims priority benefit of U.S. Patent Applications No.61/846,940, filed 16 Jul. 2013, and No. 61/941,862, filed 19 Feb. 2014,the contents of which are incorporated fully herein by reference for allpurposes.

FIELD

The embodiments described herein relate to mixing syringes. Morespecifically, these embodiments relate to syringes configured andconfigurable to enable at least one substance to be prefilled into thesyringe, or at least one substance to be filled at time-of-use by theend-user without mixing with the prefilled substance. The resultingarrangement enables syringes that are capable of storing, mixing, anddelivering of one or more substances, such as pharmaceutical substances.

BACKGROUND

The number of drugs supplied in lyophilized or powdered form has beengrowing at an increased rate over the past several years, reflecting theincrease in the introduction of biological drugs. For example, becauseof stability and shelf life factors, therapeutic proteins are oftenformulated as powders that must be reconstituted prior to injection. Agrowing number of drugs and biologics supplied in powder form areincluding reconstitution vial systems that incorporate a vial adapter orvial transfer device. Dual chamber drug cartridges and syringes go astep further and allow reconstitution to take place within the deviceimmediately prior to injection. This allows, for example, a diluent tobe added to a dehydrated, lyophilized, desiccated or powdered activesubstance immediately prior to injection, which is particularly usefulfor substances that are subject to degradation or loss of activity whenstored in a liquid form.

The majority of mixing devices for syringes utilize sequential chambers,wherein the syringe has one barrel having a proximal chamber and adistal chamber separated by, for example, a membrane or elastomericseal. A number of such sequential-chamber mixing syringes utilize abypass protrusion at a section of the barrel to enable fluid in theproximal chamber to bypass the dividing membrane and mix with the fluidor powder in the distal chamber.

Some other mixing syringes utilize concentric barrel configurations.Many concentric barrel mixing syringes to date, however, require complexassemblies, multiple operation steps by the user, or other particularnuances that make them difficult to manufacture, assemble, or operate.For example, some existing concentric barrel mixing syringes requireconcentric inner and outer barrels that are selectively rotatable withrespect to each other, and require one or more sealing rings thatcontain a passage means therein. The barrels must be rotated to align ahole in the inner barrel with the passage means in a sealing ring. Suchconfigurations require complex components and cumbersome requirementsfor the user to operate the device. Other concentric barrel designsutilize outer and inner telescopic tubular elements seated inside abarrel and coaxial with the longitudinal axis. The outer tubular elementand barrel form a chamber which holds a reservoir of liquid. The innertubular element has an end nearby the injection port with a seal thereonthat has an orifice therein. Accordingly, such mixing syringeconfigurations require three tubular elements, with the outer and innerconcentric chambers residing inside a third barrel. Still other dualchambered syringes have concentric inner and outer barrels that form anannular space to hold a fluid and utilize one or more apertures betweenthe inner and outer barrels to enable flow of a liquid from the annularspace into the inner barrel and thereby mix the liquid with a substancein the inner barrel. As with other mixing devices comprising concentricbarrels, these are also complicated in structure and often requirerotation of the barrels to align one or more apertures that enable aflow of a liquid substance from one chamber into another.

Thus, there are complexities associated with the use of concentricbarrels for mixing syringe configurations. In addition to thosedescribed above, mixing syringes utilizing concentric barrels must alsoaddress factors such as maintenance of container sterility, interactionof components for sealing, venting requirements, and distribution ofinternal forces, among other factors. As such, various sterility,sealing and venting arrangements have been used which have limitationsin terms of ease of manufacture and operation of the mixing device.Given the complexities of current drug substances, particularly relatedto sensitive biologics, there remains a need for mixing syringes thatprovide ease in manufacture, maintenance, and handling.

SUMMARY

The embodiments of the present invention provide for mixing syringesthat alleviate one or more of the problems associated with existingmixing syringes. For example, the embodiments provide for prefillablemixing syringes for maintaining, mixing, and administering substances,for example a labile pharmaceutical agent, such as a biologic.

At least one embodiment provides for a prefillable mixing syringe foradministration of at least one substance, comprising a syringe housing;a distal seal assembly axially displaceably disposed within the housing,wherein the position of the distal seal assembly defines a mutabledistal chamber and a mutable proximal chamber within the housing; thedistal seal assembly further comprising a valve that regulates a fluidpassage between the proximal and distal chambers; a plunger rodpositioned coaxially within the syringe housing and engaged with thevalve, wherein the plunger rod actuates the valve.

A further embodiment provides for a prefillable mixing syringe foradministration of at least one substance, comprising a syringe housing;a distal seal assembly axially displaceably disposed within the housing,wherein the position of the distal seal assembly defines a mutabledistal chamber and a mutable proximal chamber within the housing; thedistal seal assembly further comprising a valve that regulates a fluidpassage between the proximal and distal chambers; a plunger rodpositioned coaxially within the syringe housing and engaged with thevalve, wherein the plunger rod actuates the valve, and wherein thesyringe housing further comprises a proximal seal. At least one of theproximal seal and distal seal assembly may include a connectorconfigured to irreversibly connect the distal and proximal seals.

In a further embodiment, the syringe further includes an insert housedat least partially within the distal seal assembly, wherein the insertcomprises an internal cavity configured to engage the distal end of theplunger rod, and wherein the insert comprises at least one fluidpassage. The insert may also include at least one channel or compartmentthat regulates movement of the plunger rod within the insert. The insertmay also include a connector configured to irreversibly engage theproximal seal.

In some further embodiments, the plunger rod is configured to releasablyengage a locking mechanism to actuate the valve. The locking mechanismmay include a radial channel configured to be rotatably engaged by aplunger rod protrusion. In an alternative embodiment, a releasablelocking mechanism includes a connection for engaging the proximal sealand the plunger rod to prevent actuation of the valve, and furtherincludes a release for disengaging the proximal seal from the plungerrod.

In at least one embodiment of the prefillable mixing syringe, the distalchamber, proximal chamber, or both, contains a substance. The substancemay be or include a diluent. The substance may be lyophilized. Thesubstance may comprise a pharmaceutical agent. The pharmaceutical agentmay be, for example a biologic, a vaccine, a chemotherapeutic agent, acontrast agent, a small molecule, an immunogen, an antigen, aninterferon, a polyclonal antibody preparation, a monoclonal antibody, ananesthetic, an interfering RNA, a gene vector, an insulin, or acombination of any of these. The pharmaceutical agent may be alyophilized preparation.

In some embodiments the prefillable mixing syringe further includes adose control mechanism.

In some embodiments, the prefillable mixing syringe further includes aluer type connection at the distal end of the syringe housing.

In some embodiments, the prefillable mixing syringe further includes aretractable needle mechanism positioned in or at the distal end of thesyringe housing.

In yet another aspect, the embodiments provide for methods of assemblingthe mixing syringes described herein. In a still further aspect, theembodiments provide for methods of operating the syringes.

Another embodiment provides for a method for delivering a mixedsubstance from the prefilled mixing syringe, comprising the steps of:(a) translating the plunger rod in the proximal direction to displacethe distal end of the plunger rod from the position in which it blocksthe passage, thereby opening the passage and allowing fluidcommunication between the mutable proximal and mutable distal chambers;(b) continuing translating the plunger rod in the proximal directionuntil the distal seal meets the proximal seal, thereby displacing theproximal substance from the mutable proximal chamber into the mutabledistal chamber and mixing the proximal and distal substances; and (c)depressing the plunger rod in the distal direction, which depressingdisplaces the proximal seal and the distal seal in the distal direction,thereby expelling the mixed substances.

Accordingly, the mixing device may facilitate the storage of multiplecomponent pharmaceutical substances in the proximal and distal chambers,thereby maintaining the stability and efficacy of the pharmaceuticalsubstances during transport and over prolonged periods of storage. In aparticular embodiment of the invention, the syringe is a prefilledsyringe.

BRIEF DESCRIPTION OF THE DRAWINGS

Non-limiting embodiments of the invention are described herein withreference to the drawings.

FIG. 1A to FIG. 1E present a series of cross-sectional views, eachshowing positions of components and parts of an embodiment as theyappear in various stages of use of the embodiment.

FIG. 2A and FIG. 2B are perspective views showing an embodiment of aplunger rod distal seal assembly, comprising a plug seal incommunication with a ring seal, in which the ring seal is in the closedand open positions, such that the passage is closed (FIG. 2A), thenopened (FIG. 2B).

FIG. 3A and FIG. 3B present detailed cross-sectional perspective viewsof an embodiment of the distal seal in which the plug seal is in theclosed position (FIG. 3A) and the open position (FIG. 3B).

FIG. 4 shows a cross-sectional view showing an embodiment in which thedistal seal assembly and proximal seal assembly comprise a lockingmechanism.

FIG. 5A to FIG. 5F depict cross-sectional views of an embodiment of themixing syringe of the invention in several stages of use.

FIG. 6A to FIG. 6C present detailed views of an embodiment of a distalseal assembly.

FIG. 7A to FIG. 7E illustrate detailed cross-sectional and isometricviews of an embodiment of distal seal assembly and its components.

FIG. 8A to FIG. 8D show cross-sectional views of an embodiment of themixing syringe of the invention in several stages of use.

FIG. 9A to FIG. 9D present cross-sectional views of an embodiment of themixing syringe, comprising a dose control mechanism, in several stagesof use.

FIG. 10A to FIG. 10C depict an embodiment of a valve mechanismconfigured with a locking aspect, in the locked position for aspiration(FIG. 10A), an unlocked position (FIG. 10B), and opened position (FIG.10C).

FIG. 11A to FIG. 11G show several views of an embodiment of a syringe inwhich a locking aspect of the distal valve assembly allows the mutabledistal chamber to be filled and emptied independent of the prefilledmutable proximal chamber, providing for sequential delivery ofsubstances from the syringe.

FIG. 12A to FIG. 12D present exploded views of an embodiment of asyringe in which a locking aspect comprising the proximal valve andplunger rod configuration allows the mutable distal chamber to be filledand emptied independent of the prefilled mutable proximal chamber.

FIG. 13A to FIG. 13G present several views of an embodiment of a mixingsyringe in which a locking aspect assembly as shown in FIG. 12 allowsthe mutable distal chamber to be filled and emptied independent of theprefilled mutable proximal chamber, providing for sequential delivery ofsubstances from the syringe.

FIG. 14A to FIG. 14D show several exploded views of various positions ofa valve mechanism that allows for repeated mixing and delivery stepsfrom the same mixing syringe.

FIG. 15A to FIG. 15H present several views of an embodiment of a mixingsyringe in which a valve assembly as shown in FIG. 14 is used torepetitively mix and deliver mixed substances from the syringe.

FIG. 16A and FIG. 16B shows two views of an embodiments of a mixingsyringe that includes an actuation mechanism for needle retraction.

DETAILED DESCRIPTION

All patents and other publications identified are expressly incorporatedherein by reference for the purpose of describing and disclosing, forexample, the methodologies described in such publications that might beused in connection with the present invention. These publications areprovided solely for their disclosure prior to the filing date of thepresent application. Nothing in this regard should be construed as anadmission that the inventors are not entitled to antedate suchdisclosure by virtue of prior invention or for any other reason. Allstatements as to the date or representation as to the contents of thesedocuments are based on the information available to the applicants anddoes not constitute any admission as to the correctness of the dates orcontents of these documents.

As used herein and in the claims, the singular forms include the pluralreference and vice versa unless the context clearly indicates otherwise.Throughout this specification, unless otherwise indicated, “comprise,”“comprises” and “comprising” are used inclusively rather thanexclusively, so that a stated integer or group of integers may includeone or more other non-stated integers or groups of integers. The term“or” is inclusive unless modified, for example, by “either.” Other thanin the operating examples, or where otherwise indicated, all numbersexpressing quantities of ingredients or reaction conditions used hereinshould be understood as modified in all instances by the term “about.”

Unless otherwise defined, scientific and technical terms used inconnection with the formulations described herein shall have themeanings that are commonly understood by those of ordinary skill in theart. The terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to limit the scope ofthe present invention, which is defined solely by the claims.

The present embodiments provide for mixing syringes which generallycomprise at least a first chamber for containing a first substance and asecond chamber for containing a second substance, such that seals withinthe syringe are configured for maintaining the substances separately intheir respective chambers until such time as it is desired by a user tomix the components within the syringe by manipulating the seals toprovide fluid communication between the chambers.

References to “prefillable” generally refer to syringes comprisingcomponents for filling with a substance prior to dispensing thesubstance for its intended use. More specifically, in the context of themixing syringe embodiments, the term “prefillable” refers to aconfiguration or state in which a substance may be introduced into thesyringe any time prior to the dispensing by the syringe of thesubstance(s) for their intended use (such as delivery into a subject ordevice either directly or indirectly). A prefillable mixing syringe thusincludes syringes described herein as prefilled, fill-at-time-of-use,fill-on-demand, ready-to-use, and the like.

References to “pharmaceutical agent,” “pharmaceutically active,”“pharmaceutical,” “drug,” “medicament” “active agent,” “active drug” andthe like, refer in a general sense to substances useful in the medicaland scientific arts as suitable for delivery via a syringe, including,for example, drugs, biologics, diagnostic agents (e.g, dyes or contrastagents) or other substances used for therapeutic, diagnostic, orpreventative (e.g., vaccines), or research purposes. Examplepharmaceutical agents include biologics, vaccines, chemotherapeuticagents, contrast agents, small molecules, immunogens, antigens,interferons, polyclonal antibody preparations, monoclonal antibodies,anesthetics, interfering RNAs, gene vectors, insulins, or combinationsof any of these. “Inactive” substances refer to carriers, excipients,diluents, and the like, which are well-known in the art, although suchsubstances may have beneficial function in the mixed injectable, suchas, for example, adjuvants, isotonic or buffering agents. These activeor inactive substances may also include substances having immediate,delayed or sustained release characteristics.

“Fluid” refers primarily to liquids, but can also include suspensions ofsolids dispersed in liquids (dispersions, suspensions, colloidalmixtures), emulsions, liposomal compositions, and gasses dissolved in orotherwise present together within liquids inside the fluid-containingportions of syringes.

As used herein to describe the relative positions of the components ofthe present embodiments, the terms “axial” or “axially” refer generallyto a longitudinal axis “A” of the barrel of the syringe and plunger inwhich or around components are positioned, although not necessarilysymmetrically there-around. The term “radial” refers generally to adirection perpendicular to axis A. The terms “proximal,” “rear,”“rearward,” “back,” or “backward” refer generally to an axial directionin the direction “P.” The terms “distal,” “front,” “frontward,”“depressed,” or “forward” refer generally to an axial direction in thedirection “D,” toward the dispensing end of the syringe.

As used herein, the term “glass” should be understood to include othersimilarly non-reactive materials suitable for use in a pharmaceuticalgrade application that would normally require glass (e.g., Type Iborosilicate glass), including but not limited to certain non-reactivepolymers such as cyclic olefin copolymers (COC) and cyclic olefinpolymers (COP).

The term “plastic” may include both thermoplastic and thermosettingpolymers. Thermoplastic polymers can be re-softened to their originalcondition by heat; thermosetting polymers cannot. As used herein, theterm “plastic” refers primarily to moldable thermoplastic polymers suchas, for example, polyethylene and polypropylene, or an acrylic resin,that also typically contain other ingredients such as curatives,fillers, reinforcing agents, colorants, or plasticizers, etc., and thatcan be formed or molded under heat and pressure. As used herein, theterm “plastic” can include pharmaceutical grade non-reactive polymers orelastomers that are approved for use in applications where they are indirect contact with therapeutic substances, such that the plastics donot interact with the substances contacting the plastic and are notreadily susceptible to leaching or gas migration under ambienttemperature and pressure.

The term “elastomer,” “elastomeric” or “elastomeric material” refersprimarily to cross-linked thermosetting rubbery polymers that are moreeasily deformable than resilient plastics, are approved for use withpharmaceutical grade substances, and are not readily susceptible toleaching or gas migration under ambient temperature and pressure.

The present embodiments provide for mixing syringes in which a distalseal assembly maintains substances in separate, mutable chambers until auser displaces a plug seal within the distal seal assembly, opening apassage within the distal seal assembly and allowing the separatedsubstances to mix within the syringe. Prefilled mixing syringes areadvantageous in avoiding confusion whether a vial is multidose or singledose, or confusion regarding which diluent should be used with a givenlyophilized or powder medicament. Additional embodiments provide forsyringes in which one mutable chamber is configured to be prefilled, andanother mutable chamber is configured to be loaded at or near thetime-of-use.

In one aspect, the embodiments provide for a mixing syringe having asyringe housing with a proximal end and a distal end, and a mutableproximal chamber and a mutable distal chamber defined within the syringehousing. The syringe includes a plunger rod configured to translatesubstantially axially within the barrel of the housing and between theproximal end and distal end of the housing to deliver one or moresubstances. The distal end of the housing may be configured to connectto, or be connected to, a needle, cannula, or other conduit for fluidtransfer from the mixing syringe to a subject, patient, intravenous(i.v.) line, fluid tube, container, scientific instrument, or the like.In at least one embodiment, the distal end of the housing has a luertype connection, such as a luer lock connection, for connection of thebarrel to a vial, container, needle, or i.v. line. The syringe furtherincludes a distal seal assembly, and at least a portion of distal end ofthe plunger rod may be engaged with the distal seal assembly. The distalseal assembly may comprise a valve-type seal, wherein a portion of theseal assembly may move with reference to the remainder of the sealassembly to open and close one or more passages within the distal sealassembly, thus permitting an operator to effect fluid communicationbetween the mutable distal chamber and the mutable proximal chamber. Themutable chambers are defined by the position of the distal seal assemblywithin the housing, and by the distal or proximal interior walls of thehousing, by suitable seals located within the housing, or by a proximalseal assembly that can be configured to engage with the distal sealassembly. In at least one embodiment, the valve-type seal of the distalseal assembly has an inner plug seal oriented axially within an outerring seal, such that a passage is closed when the plug seal and ringseal are in a first position, and the passage is opened when the plugseal is moved into a second position at least partially apart from thering seal. The plug seal may be attached to or be an aspect of (e.g., aregion of) the distal end of the plunger rod. The distal seal assemblymay optionally include a locking aspect capable of locking thevalve-type seal. The distal seal assembly may comprise an insert thatprovides at least part of the structure of the valve-type mechanism orlocking aspect.

The distal seal may optionally have a connector that facilitatesconnection between the distal seal assembly and the proximal seal oncethe distal seal has been proximally translated to meet the proximalseal. Alternatively, the distal seal and the proximal seal may beconnected or held in connection by a vacuum created there-between orpressure from the chamber containing the mixed substances, with orwithout the use of such an optional connector/connection feature. Inthese embodiments, when the distal seal engages the proximal seal byconnection (e.g., via a connector) or physical forces within the syringe(e.g., vacuum), the proximal seal and the distal seal may translateaxially within the barrel as if a unified component. In at least oneembodiment, the proximal seal is retained in a substantially fixedposition within the housing until connection with the distal seal.Accordingly, once the distal and proximal substances have been mixed,translation of the plunger rod in the distal direction can translateboth the proximal and distal seals in the distal direction to force themixed substance from the distal end of the housing.

In at least some embodiments, the mutable proximal chamber and themutable distal chamber may contain one or more mixing substances, i.e.,first and second mixing substances (or distal and proximal substances),which substances may each be a powder, crystal, solid, fluid, liquid,suspension, gas, or other substances suitable for mixing. One of more ofthe substances can be pharmaceutically active. The substance in themutable proximal chamber and the mutable distal chamber may be prefilledor filled on-demand, such as near or at the time of use.

In at least one embodiment, as the operator translates the plunger rodin the proximal direction, the plug seal is (optionally, temporarily)moved into a second position partially apart from the distal sealassembly, e.g., apart from the distal ring seal or an insert therein,such that the passage is opened. As the operator withdraws the plungerrod, the passage may remain open for the transfer of substances betweenportions of the barrel that are proximal and distal (or vice versa)through the distal seal assembly. In this way, the distal seal assemblydefines mutable proximal and distal chambers within the barrel, andfacilitates the movement of substances between the mutable proximal anddistal chambers.

In at least one embodiment, the mixing of the substances is facilitatedby creating a pressure differential between the mutable proximal chamberand the mutable distal chamber.

In one or more embodiments, the syringe may be configured to enable aprefilled arrangement or a fill-at-time-of-use arrangement. For example,during the manufacturing process at least one of the chambers of themixing syringe may be prefilled with one or more mixing substances.Alternatively, one or more chambers may be prefilled, while one or moreother chambers are configured to be filled on-demand, e.g., filled justprior to use. For example, in at least one embodiment, the mutableproximal chamber of the mixing syringe comprises a proximal substance,and the mutable distal chamber is configured to be filled on-demandprior to use, or at the time use, by an end-user, for instance aphysician, pharmacist, nurse, caregiver, patient, or the like. Inanother alternative, both chambers may be configured to be filledon-demand, e.g., filled just prior to use. In this embodiment, thesyringe can be oriented so that gravity assists the loading of asubstance into the proximal chamber (P) via the distal chamber (D). Thedistal chamber may then be loaded with the same or a different substance(including differing concentrations, potencies, formulations and thelike, of the same substance). Such arrangements may be facilitated bythe use of one or more locking mechanisms that function to enable thevalve-type seal to remain closed during some stages of operation (suchas for filling), but permit the valve-type seal to open a fluid passagetherethrough during other stages of operation (such as for mixing). Inat least one embodiment, the mixing syringe comprises a lockingmechanism that allows for sequential delivery of substances with orwithout mixing or repetitive mixing of the substances.

In some embodiments, the proximal and distal chambers can be prefilledto contain one or more mixing substances, i.e., proximal and distalmixing substances, which may each be a powder, solid, liquid,suspension, gas, or mixtures of these substances. For example, thedistal mixing substance locatable in the distal chamber may be a fluidthat comprises a pharmaceutically active fluid or a pharmaceuticallyinactive fluid, such as a diluent. The proximal mixing substancelocatable in the proximal chamber may be a fluid that comprises apharmaceutically active fluid or a pharmaceutically inactive fluid, suchas a diluent. Alternatively, for example, the proximal substancelocatable in the proximal chamber may comprise a pharmaceutically activesolid or an inactive solid excipient, and the distal substance maycomprise a pharmaceutically active fluid or a pharmaceutically inactivefluid; or the proximal substance in the proximal chamber may comprise apharmaceutically active fluid or a pharmaceutically inactive fluid, andthe distal substance may comprise a pharmaceutically active solid or aninactive solid excipient. As is well understood in the art, apharmaceutically active component may be mixed with suitable excipientsin its respective mutable chamber in the prefilled syringe. For example,a powdered drug is often lyophilized with salts, sugars, or polyols,such as mannitol or lactose; a liquid drug is often formulated inethanol, buffers, or non-aqueous or aqueous solvents.

In one embodiment, for example, a first mixing substance locatable inthe mutable distal chamber may be fluid, and a second mixing substancelocatable in the mutable proximal chamber may also be a fluid. One orboth of the fluids may be pharmaceutically active. Alternatively, forexample, the first mixing substance locatable in the mutable distalchamber (a distal substance), may be a solid. The solid may be apharmaceutically active solid, such as a biologic, drug or dye, or apharmaceutically inactive solid such as an excipient. The second mixingsubstance locatable in the mutable proximal chamber (a proximalsubstance), may be, for example, a fluid. The fluid may be apharmaceutically active fluid, such as a biologic, drug or dye, or apharmaceutically inactive fluid, such as a diluent. Alternatively, thefirst substance locatable in the distal chamber may be a fluid, and thesecond mixing substance, locatable in the proximal chamber, may be asolid. When the mutable distal chamber is filled with a fluid, thechamber may be prefilled or filled on-demand, such as near or at thetime of use.

In one embodiment, the mutable distal chamber contains apharmaceutically active solid and the mutable proximal chamber containsa pharmaceutically inactive liquid diluent, such as water for injection,whereby entry of the diluent through the passage of the distal sealassembly, once opened, facilitates mixing of the diluent with thepharmaceutically active solid. The mixing of the diluent and thepharmaceutically active solid enables reconstitution of thepharmaceutically active solid for, as an example, subsequent delivery ofpharmaceutically active compound to a patient.

In another embodiment, the mutable distal chamber contains apharmaceutically active solid and the mutable proximal chamber containsa pharmaceutically active fluid, whereby entry of the fluid through thepassage in the distal seal assembly, once opened, facilitates mixingwith the pharmaceutically active solid in the distal chamber. The mixingof the pharmaceutically active fluid and the pharmaceutically activesolid enables reconstitution of the pharmaceutically active solid for,e.g., subsequent delivery of both pharmaceutically active compounds to apatient.

In yet another embodiment, the distal chamber contains a firstpharmaceutically active fluid and the proximal chamber contains a secondpharmaceutically active fluid, whereby entry of the firstpharmaceutically active fluid through the passage facilitates mixingwith the second pharmaceutically active fluid in the distal chamber. Themixing of the first pharmaceutically active fluid and the secondpharmaceutically active fluid enables mixing of the pharmaceuticallyactive fluids, e.g., for subsequent delivery of both pharmaceuticallyactive compounds to a patient.

In another embodiment, at least one of the chambers of a mixing syringemay be filled just prior to use, such as by the physician, pharmacist,nurse, caregiver, patient, end-user, or the like. Similarly, one or morechambers may be pre-filled, while one or more other chambers are filledjust prior to use. Such an arrangement may be facilitated by the use ofone or more locking mechanisms. The locking mechanisms function toenable the valve-type seal to remain closed during some stages ofoperation (such as for filling), but permit the valve-type seal to opena fluid passage therethrough during other stages of operation (such asfor mixing or for dispensing an unmixed fluid from the proximalchamber). For example, a locking mechanism may be configured in thevalve mechanism/assembly. Alternatively, a locking mechanism can beconfigured apart from the valve mechanism, such as in a plunger/proximalseal latch/release system. When the locking feature is engaged, and thedistal chamber loaded, the distal substance can be expelled withoutmixing. When the locking feature is disabled, the device operates muchthe same way as the above embodiments (i.e., withdrawing the plunger rodin the proximal direction opens the fluid path to allow mixing). Afterthe distal chamber is filled, the syringe is ready for the mixingfeature, and the plunger rod may be further translated in the axialdirection to open the fluid passage within the distal seal for mixingsubstances. The plunger rod becomes disengaged from the proximal seal toallow for this mixing to occur. Thereafter, the plunger rod can betranslated axially in the distal direction for drug delivery.Additionally, when the locking feature (of the distal or proximal seals)are maintained in the closed/locked position, the syringe can be used toload and deliver fluid from the distal chamber independent of theproximal chamber and without mixing with the proximal chamber, allowingfor sequential delivery of fluids (e.g., unmixed, then mixed; or a firstfluid from the distal chamber, then a second fluid from the proximalchamber) from the same syringe.

Another embodiment provides for a valve mechanism that allows forpartial and repeated mixing steps within the same mixing syringe. In aparticular embodiment, an intermediate open/closed position in the valveallows for repeated proximal/distal translation of the plunger whichsuccessively mixes proximal and distal substances until the mutableproximal chamber is collapsed and any remainder of proximal substance ismixed with the distal substance. This feature allows the relativeconcentrations of the distal and proximal substances to be uniform asthe proximal and distal substances are mixed and the mixed substancesare expelled from the mixing syringe. This feature also allows therelative concentrations of the distal and proximal substances to vary(e.g., from more concentrated distal substance relative to proximalsubstance, to less concentrated distal substance relative to proximalsubstance) as the proximal and distal substances are mixed and the mixedsubstances are expelled from the mixing syringe. An additional featureemploys a locking mechanism that allows optional independent loading anddelivery from the mutable distal chamber before employing the mixingfeature of the syringe.

An additional aspect of the present invention provides for mixingsyringes further capable of connecting to selectable needle assemblies,or to a needleless access device such as an i.v. line. Particularembodiments of such devices are described in U.S. Patent ApplicationsNo. 61/934,963, filed 3 Feb. 2014; No. 61/898,077, filed 31 Oct. 2014;and No. 61/863,098, filed 7 Aug. 2013, each of which is incorporatedfully herein for all purposes. The connection aspect may be pre-formedas a distal portion of the syringe barrel housing. Alternatively, thesyringe barrel may be a substantially straight barrel to which aconnection adapter is mounted. An adapter mountable to a syringe barrelmay have a luer connection portion and a barrel-engaging portion and afluid aperture therethrough. The adapter facilitates mounting a luerassembly to the barrel. The luer assembly may be a tip cap having acorresponding female luer fitment for connection to the male luerfitment of the luer connection portion of the adapter. The luer assemblymay alternatively be a luer needle assembly having a needle body,cannula, and a needle tip having a corresponding female luer fitment forconnection to the male luer fitment of the luer connection portion ofthe adapter. The adapter and syringe may further comprise an immobile,compressible needle seal, which is adjacent to or engageable with thebarrel-engaging portion of the adapter. For example, a needle seal sitswithin the interior of the barrel or adapter, and has a fluidpass-through axially located for the passage of fluid.

In at least one embodiment, the syringe is a retractable syringe thatcomprises a retractable needle.

In at least one embodiment, the plunger may be a conventional plunger.In another embodiment, the plunger is an accurate dose delivery plunger.

The present embodiments are particularly useful for the administrationof lyophilized pharmaceuticals, including small molecules andbiologicals, such as those presently marketed as lyophilized or powdereddrugs for injection. These include, by way of non-limiting examples,ActHIB® vaccine, Aldesleukin, ampicillin, asparaginase, amphotericin B(Amphotec, Amphocin, others), ATryn antithrombin, Bendamustine,Bleomycin, Bortezomib, Carboplatin, Carmustine, Caverject Powder(Alprostadil), Certolizumab (CIMZIA®), Cefazolin, Cefonicid,Ceftazidime, Ceftriaxone sodium, Cisplatin, Cytarabine, Cytoxan(cyclophosphamide), Dacarbazine, Daunorubicin, Degarelix,Desferrioxamine Mesilate, Doxorubicin (Adriamycin), Epirubicin,Erythrocin lactobionate, estrogen, Gemcitabine, glucagon, humanchorionic gonadotropin, human growth hormone, human menopausalgonadotropin (HMG, menotrpin), human plasma, HcG 50001U-5ml, immuneglobulin (Carimune, Gammagard®), Interferon beta-la (Avonex), Intron A(interferon alfa-2b), Kogenate FS (recombinant factor VII) Leucovorincalcium, leuproreline, methylprednisolone, Leukine (sargramostim),Menomune® vaccine, MMR and MMRV vaccines, Peginterferon alfa-2b(PegIntron), Remicade® infliximab, Sermorelin/GHRH6-5ml, somatropin(Genotropin, Saizen®), Sincalide (Kinevac), thiotepa, Vecuroniumbromide, Vfend (voriconazole), Vincristine, Varicella vaccines, andZostavax.

Some excipients are included in powdered or lyophilized products, suchas solubilizers or buffers, may be considered functional excipients.Excipients used in various lyophilized formulations include bulkingagents, buffering agents, tonicity modifiers, antimicrobial agents,surfactants and co-solvents, and are well-known in the art. See, e.g.,Baheti et al., Excipients Used in Lyophilization of Small Molecules, 1J. Excipients & Food Chem. 41 (2010). Similarly, diluents are well-knownin the art, such as water for injection, and often include excipients,e.g., saline or Ringer's solution.

In one embodiment, a method of operation of a mixing syringe prefilledwith proximal and distal substances includes the steps of: (a) drawingback on the plunger rod, thereby disengaging the distal end of theplunger rod within the distal seal assembly to open a fluid path betweenthe proximal and distal chambers, which allows flow of the proximalsubstance from the mutable proximal chamber into the mutable distalchamber, thereby mixing the two substances; (b) continuing the drawingof the plunger until the distal seal assembly and proximal seal meet andlock together (the system now has only one chamber; mixing is complete);and (c) pushing the plunger rod to expel the mixed substances.

In another embodiment, a method of operation of a mixing syringeprefilled with proximal and distal substances includes the steps of: (a)drawing back on plunger rod thereby disengaging the plug seal from thedistal seal to open a fluid path between the prefilled chambers (b)inverting the syringe to allow flow of the distal substance from themutable distal chamber into the mutable proximal chamber, thereby mixingthe two substances; (c) continuing the drawing until distal sealassembly and proximal seal meet and lock together (the system now hasonly one chamber; mixing is complete); and (d) pushing the plunger rodto deliver mixed substances.

In another embodiment, a method of operation of a syringe having aprefilled mutable proximal chamber includes the steps of: (a) drawingdistal substance (e.g., drug or diluent) by pulling proximally on theplunger rod while the plunger rod is locked in position such that avalve between the distal and proximal chambers remains closed, creatingand filling a mutable distal chamber; (b) rotating the plunger rod to anunlocked position and drawing back on plunger rod to open a fluid pathbetween distal and proximal chambers, which allows flow of proximalsubstance from the prefilled proximal chamber into the distal chamber inwhich the distal substance was drawn from step (a), thereby mixing thetwo substances; (c) continuing to draw the plunger rod proximally untilthe distal seal assembly and the proximal seal meet and lock together(the system now has only one chamber; mixing is complete); and (d)pushing the plunger to deliver mixed drug substances.

In yet another embodiment, a method of operation includes the steps of:(a) drawing a distal substance (e.g., drug or diluent) into distalchamber by pulling on the plunger rod to create mutable distal chamber;(b) disabling the locking feature that locks motion of the plunger withmotion of the proximal seal thus disengaging the proximal seal from theplunger rod; (c) drawing back on plunger rod to allow flow of theprefilled proximal substance into the distal chamber thereby mixing theproximal and distal substances; (d) continue drawing the plunger rodproximally until the distal seal assembly and proximal seal meet andlock together (the system now has only one chamber; mixing is complete);and (e) pushing the plunger to deliver mixed substance.

An alternative method of operation of a mixing syringe having aprefilled proximal chamber includes the steps of: (a) drawing a distalsubstance into the mutable distal chamber by pulling on the plunger rod;(b) pushing on the plunger to expel the distal substance; (c)optionally, repeating steps (a) and (b); (d) drawing a distal substanceinto the mutable distal chamber; (e) disabling a locking feature toallow fluid communication of the proximal substance from the mutableproximal chamber; (0 pulling proximally on the plunger rod to displacethe proximal substance until the distal seal assembly and the proximalseal meet and lock together, resulting in fully mixed substance; and (g)pushing the plunger to deliver the fluid.

Yet another alternative method of operation of a mixing syringe having aprefilled proximal chamber includes the steps of: (a) drawing a distalsubstance into the mutable distal chamber by pulling on the plunger rod;(b) optionally, pushing on the plunger to expel the distal substance;(c) optionally, repeating steps (a) and (b); (d) drawing a distalsubstance into the mutable distal chamber; (e) disabling a lockingfeature to allow fluid communication of the proximal substance from themutable proximal chamber; (f) repeatedly (e.g., at least once)alternately pulling and pushing the plunger rod to mix and expelsuccessively mixed substances comprising a successively lessconcentrated distal substance/successively more concentrated proximalsubstance; (g) pulling proximally on the plunger rod to displace theproximal substance until the distal seal assembly and the proximal sealmeet and lock together, resulting in fully mixed substance, in which thesubstance comprises different concentrations of distal and proximalsubstances compared to a method in which step (f) was not practiced; and(h) pushing the plunger to deliver remainder of the mixed fluid.

Referring to the figures, FIG. 1A shows an embodiment of a preloadedmixing syringe 10 having a housing comprising housing 20, configuredsimilar to a typical syringe. The housing can be glass or plastic or anysubstance suitable for use in the storage of pharmaceutical-gradesubstances as are known in the art. Housing 20 contains a first, distalsubstance 70 in a mutable distal chamber 75, and a second, proximalsubstance 72 in a mutable proximal chamber 73, mutable chambers aredefined by a position of distal seal assembly 40 and a position of theproximal seal 60 within housing 20. The distal end 22 of housing 20generally has a reduced diameter opening forming a discharge opening.Distal end 22 of housing 20 typically comprises means to maintain thedistal end closed, capped or covered, for example by tip cap 23, suchthat and the syringe contents are maintained in aseptic condition, andmeans to attach the mixing syringe to a hypodermic needle, luer lock, orsuitable engagement for delivery of contents to the desired target. Thedistal end of the barrel may have a needle, cannula, or other conduitfor fluid transfer to a user, to an intravenous (i.v.) line, fluid tube,or container, or the like. In at least one embodiment, the distal end ofthe barrel has a luer type connection, such as a luer lock connection,for connection of the barrel to a drug container, needle, or i.v. line.The proximal end of housing 20 is configured to receive and houseplunger rod 30, axially displaceable within the barrel of housing 20,distal seal assembly 40 and proximal seal 60. The proximal end ofhousing 20 of the mixing syringe includes a radial flange 21 that maycomprise a continuous circumferential flange or be pair of opposingflanges, projecting outwardly from housing 20, and forming a grippingelement. It should be noted, however, that the embodiments herein arenot limited to any particular type of syringe housing, as the featuresof the mutable chambers defined by the valved distal seal assembly orproximal locking mechanism are adaptable to a variety of syringehousings.

Plunger rod 30 can be glass, plastic, plastic coated with silicon oxideor plastic coated with barrier coatings such as parylene and the like,or any suitable material typically known in the art. The distal end ofplunger rod 30 comprises plug seal 32 (or similar means) configured todisplaceably engage a cavity within ring seal assembly, and which servesto maintain closure of the valve mechanism until displaced by anoperator to allow mixing of substances 70 and 72. The proximal end ofplunger rod 30 comprises grip 39 that projects outwardly as acircumferential flange from plunger rod 30 and provides a grippingelement for the operator to use for manipulating the position of plunger30. Proximal seal 60 is an elastomeric element displaceably situatedproximally within housing 20 and configured to engage with distal sealassembly 40 when distal seal assembly 40 is in the most-proximalposition, thereafter pressure on plunger grip 39 in the axial, distaldirection moves plunger rod 30 and both proximal 60 and distal 40 sealsin the distal direction and expels contents of syringe 10 throughopening 22 on distal end of housing 20.

Distal seal assembly 40 comprises ring seal 42, an elastomeric elementcomprising circumferential ribs 43 that forms a fluid-tight seal withthe interior wall of the housing 20, and maintains a first substance 70in a mutable distal chamber 75 that is defined by the position of distalseal assembly 40 within housing 20. Ring seal 42 and distal ribs 43 areconfigured to be moved axially within housing 20 when sufficient pull orpush is applied to plunger rod 30, typically at grip 39. The grip of theplunger rod can be a flange, a ring, or any structure that allows theend-user to move the position of the plunger within the housing of thesyringe.

In an embodiment of the invention, as shown in FIG. 1A, distal sealassembly 40 includes ring seal 42 and insert 50, configured to engageplug seal 32, which plug seal 32 is connected with or mounted to thedistal end of plunger rod 30. Insert 50 can be made from polymer (e.g.,plastic) or glass that is resilient to deformation. In the embodiment ofFIG. 1A, distal seal assembly 40 also contains at least one passage 54extending longitudinally through the interior of insert 50, configuredto allow substance 72 to flow or otherwise move from proximal chamber 73and mix with substance 70 in distal chamber 75, or vice versa, whenpassage 44 is opened by displacement of plug seal 32 from a distalposition “closed” (FIG. 1A) to a proximal position “open” (FIG. 1B)within the distal seal assembly 40. In other words, passage 44 is closedwhen plunger rod 30 is in its farthest distal position within distalseal assembly 40 and plug seal 32 is engaged with or tightly abutted tothe distal portion of ring seal 42, or most-distally disposed withininsert 50, as shown in FIG. 1A. In the configuration shown in FIG. 1A,the first 70 and second 72 substances are unable to contact each otherwhen plug seal 32 is in the distal-most position within distal sealassembly 40 (e.g., the most distal position within ring seal 42 andinsert 50). The first 70 and second 72 substances can be mixed to formmixed substance 78, however, by displacement of plunger rod 30 axiallyin the proximal direction P, as shown by the arrow in FIG. 2B, such thatplug seal 32 is displaced within ring seal 42 or insert 50 to openpassage 54. In at least one embodiment, the proximal seal is retained ina substantially fixed position within housing 20 until connection withthe distal seal for delivery of the mixed substance 78, or when theproximal substance and distal substance are mixed, or the delivery ofproximal substance 72.

The force required to displace plug seal 32 from the closed position tothe open position is less than or equal to the force required todisplace distal seal assembly 40 within housing 20. Thus, the user oroperator should not be able to easily displace the distal seal assemblywhen the valve is closed. Although plunger rod 30 and plug seal 32 areconfigured to be retracted within the ring seal 42, plunger rod 30remains engaged with distal seal assembly 40, being restricted within acompartment within insert 50, such that once the passage 54 is opened bydisplacement of plug seal 32 within ring seal 42, the entire distal sealassembly 40 can be moved axially within housing 20, for example in theproximal direction P by proximal movement of the plunger, as shown inFIG. 1C. Movement of distal seal assembly 40 within housing barrel 20 byaxial, proximal movement of plunger rod 30 also forces displacement ofsubstance 72 from the shrinking proximal chamber 73 into growing distalchamber 75 via passage 54, until the mutable chambers have merged intoone chamber and substances 70 and 72 have mixed to form mixed substance78.

When plunger rod 30 is moved fully to the proximal end of housing 20, asshown in FIG. 1D, the mutable distal and proximal chambers have mergedwithin housing 20, which then contains mixed substance 78; and distalseal assembly 40 engages proximal seal 60. The engagement between distalseal assembly 40 and proximal seal 60 is such that when plunger rod 30is moved from the fully proximal position, axially in the distaldirection D, as indicated by the arrow in FIG. 1E, both distal sealassembly 40 and axial seal assembly 50 move in unison and expel mixedsubstance 78 through the distal end 22 of housing 20.

FIG. 2A shows a perspective view of an embodiment of plunger rod 30 anddistal seal assembly 40, in which plug seal 32 is positioned at thedistal end of ring seal 42 in the closed position. FIG. 2B shows a viewof plunger rod 30 and ring seal 42 in which passage 44 is open (the plugseal has been displaced proximally, i.e., retracted, into ring seal 42).Distal seal assembly 40 may comprise a circumferential O-ring or lip inthe circumferential ribs 43 that bear against the inner wall of housing20 (not shown) to create greater resistance to, and regulation of,movement of distal seal assembly 40 compared with retraction of plugseal 32.

FIG. 3A and FIG. 3B show detailed perspective views of and embodiment ofa distal seal assembly 40. Ring seal 42 comprises circumferential ribs43 configured to bear against the interior of the housing 20 wall (notshown) and provide a fluid-tight seal between distal seal assembly 40and inside wall of barrel housing 20, and resistance against accidentalmovement of distal seal within barrel of housing 20. Movement of distalseal 40 within housing 20 can also be impeded by vacuum or pressure inthe appropriate distal or proximal chambers. When plug seal 32 isdisposed in ring seal 42 in the “closed” position, plunger rod 30 can bedisplaced proximally relative to ring seal 42, but plunger rod 30 cannotbe further displaced distally relative to the distal end of distal sealassembly 40. For example, motion of plug seal 32 can be limited withinring seal 42 by configuration of complementary facing tapered distalends of the exterior of plug seal 32 and interior of ring seal 42; or byplacement of a threaded connection, interior-facing projections, orother structures. For example, ring seal 42 is fitted with insert 50,which is stabilized within ring seal 42 by a protrusion fitting 55 thatfits in a complementary recessed step 45 within ring seal 42. Plug seal32 is connected to plunger rod 30 by conventional means, such as glue orcomplementary screw threads or snap-lock engaging means. Plug seal 32comprises exterior annular ribs 35 that releasably engage the interiorof insert 50 by means structures such as a protrusion and recess orthreaded screw, or plug seal 32 and annular ribs 35 may simply bearagainst the interior wall of insert 50 such that movement is impededuntil the user engages in proximal displacement of plug seal 32. Priorto use (i.e., prior to mixing), annular ribs 35 of plug seal 32 blockpassage 44 and the first and second substances cannot mix. To preparethe device for use, i.e., initial mixing of proximal substance 72 withdistal substance 70, the operator displaces plunger rod 30 proximallyrelative to distal seal assembly 40, typically by pulling on plunger rodgrip 39, thereby displacing plug seal 32 within insert 50 and openingpassage 44, as shown in FIG. 3B. In an alternative embodiment, annularribs 35 and annular steps 45 are configured as complementary male andfemale threads, such that plug seal 32 is moved from the distal-mostposition within distal seal assembly 40 by a twisting, limited“unscrewing” motion of plunger rod 30.

Distal seal assembly 40 and plunger rod 30 may also comprise means toimpede further proximal motion of plunger rod 30 from distal sealassembly 40 such that plug seal 32 cannot be removed readily from insert50, and plunger 30 is substantially permanently attached to distal sealassembly 40. For example, as shown in FIG. 4A and FIG. 4B, plunger rod30 comprises a flanged region or pair of barbs 36, configured to engagea complementary recess 56 in insert 50, such that when plunger rod 30 ismoved axially, plug seal 32 is proximally displaced and passage 44 hasbeen opened, barb 36 engages recess 56 which impedes further substantialproximal movement of plug seal 32 within distal seal assembly 40.Alternatively, the device can be configured such that annular rib 35engages with annular recess 46; via a complementary threaded connection;or via a cross section comprising a series of proximally tapered annularsteps that engage complementary annular ribs inside the distal sealassembly 40. Once plug seal 32 has been retracted such that passage 44is opened, further proximal motion of plunger rod 30 moves entire distalseal 40 in the proximal direction within the barrel of housing 20.

Referring to FIG. 4, in this embodiment distal seal assembly 140comprises ring seal 142, which holds an insert having a fluid passage154 that is opened when plug seal 132 is in the proximal position (asshown), and further comprises projecting connector 158 configured tomate with a complementary recessed connection 168 formed in proximalinsert 161 in proximal seal 160. The connector may comprise otherproximal seal engaging means, such as complementary screw threads or asnap-lock protrusion and complementary snap-lock recess to form alocking mechanism that facilitates connection of distal seal assembly140 and proximal seal 160, such that once engaged by motion of plungerrod 130 to the most-proximal position, seals 140 and 160 areirreversibly joined and then respond in tandem to depression of plungerrod 30, similar what is shown in FIG. 1E.

Another embodiment of distal and proximal seal assemblies of the mixingsyringe are shown in FIG. 5A to FIG. 5F, with details of the distal ringseal, insert and plug seal illustrated in FIG. 6A and FIG. 6B. In thisembodiment of a preloaded syringe, plunger rod 230 includes engagingmeans 231 in the form of a complementary screw/thread in plug seal 232,which engages plunger rod 230 with plug seal 232, as shown in FIG. 6C.Plunger 230 further comprises a radial collar or flange 236, configuredto limit movement of the plug seal within the confines (interiorcompartment) of insert 250 and maintain the connection between plungerrod 230 and distal seal assembly 240. Note that the mixing syringe ofFIG. 5A is depicted with stopper 223 positioned in the distal end 22 ofbarrel housing 20, which is replaced by needle assembly 28 in FIG. 5F,in which mixed substance 78 is injected, via threads 27. The embodimentshown in FIG. 5 also comprises a syringe cap assembly 224 abuttingflanged grip 21 and sealing the prosimal end of the mixing syringe. FIG.5A and FIG. 6B show the distal seal assembly is in the “closed”position, in which plug seal ribs 235 bear against distal channel 252formed by the interior wall of insert 250, which channel is visible oncethe plug seal is moved into the “open” position as shown in FIGS. 5B and6B. Further distal movement of plug seal 232 is impeded by distal edge257 formed by the interior walls of insert 250, which stops radialflange 236 from distal movement within insert 250. Insert 250 isstabilized within ring seal 242 by at least one protruding radial flangeor shoulder 255 that fits into complementary ring seal step 245.

In the view of FIG. 5B and FIG. 6B, proximal motion of plunger rod 230has displaced plug seal 232 from channel 252 and into channel 253(hashed in FIG. 5A) in insert 250. Distal seal assembly 240 maintainsposition in housing 20 by pressure of radial ribs 243 against theinterior wall of housing 20. The position of plug seal 232 away fromchannel 252 and into channel 253 (i.e., retracted into the distal sealassembly) unblocks opening 259 in passage 254 (hashed), such that thevalve function of distal seal assembly 240 is “open,” which allowscommunication between mutable distal chamber 70 and mutable proximalchamber 80. Further proximal motion of plunger rod 230 is impeded byplunger rod flange 236 abutting proximal ledge 256 of the insertcompartment formed by the proximal interior wall of insert 250.

As shown in FIG. 5C, once passage 254 has been opened, the user maycontinue to displace plunger rod 230 in the proximal direction, which inturn displaces seal assembly 240 in the proximal direction, displacingsubstance 72 from the shrinking proximal chamber 73 through passage 254and into growing distal chamber 75, such that substance 72 combines withsubstance 70 to form mixed substance 78. In this embodiment, the user isnot able to pass substance 78 back through passage 254 as a means ofmixing, because distal pressure of plunger rod 30 may close the valvebefore distal assembly 240 moves in the distal direction. In alternativeembodiments, however, displacement of a distal plug seal can be achievedusing a locking mechanism, e.g., a screw-thread mechanism or snap-lockmechanism, such that the open position remains fixed during subsequentdistal pressure on plunger rod 30. In the embodiment of FIG. 5D, ifrequired to ensure adequate mixing, the user can shake, swirl or vortexthe syringe to achieve substantial or complete mixing, dissolving,dispersing or suspending of mixed substances 78.

Also shown in the FIG. 5 series is a connecting mechanism, connector258, configured to connect distal seal assembly 240 with proximal seal260, further details of which are shown in FIG. 6C. In this embodiment,the connection between distal seal assembly 240 and proximal sealassembly 260 is configured to be permanent or otherwise difficult todislodge. Proximal seal assembly 260 comprises radial ribs 263, whichbear against the inner wall of housing 20 to impede movement of proximalseal 260 until the operator engages it with distal seal assembly 240.Proximal seal 260 comprises rigid insert 261 held in place withinproximal seal 260 by protrusions 265 extending outwardly therefrom intocomplementary annular steps 264 within proximal seal 260. The interiorwall of insert 261 comprises recess 268, a connection configured toreceive and connect with connector 258 when distal seal assembly 240reaches the proximal-most position as shown in FIG. 5D.

As shown in FIG. 5D, once plunger rod 330 has been maneuvered into theproximal-most position within housing 20, the mutable proximal anddistal chambers have merged and housing 20 holds mixed substances 78. Inthis position, plug seal 232 is still in the proximal open position,although proximal seal 260 is a fluid-tight seal. Proximal displacementhas caused connector 258 to mate with connection 268, such that distalseal assembly and proximal seal 260 are connected. Thereafter, to ensurethat little or no substance 72 or mixed substances 78 remains in insert250, and to close the valve, the user exerts distal pressure on plungerrod 230, for example by depressing plunger rod interface 239, therebydisplacing seal plug 232 distally into channel 252, closing passage 244as shown in FIG. 5E and FIG. 6C. In FIG. 5E, distal seal assembly 240 islocked into connection with proximal seal 260 and the valve is closed;in the position where mixed substance 78 can be expelled from mixingsyringe. Thus, the user can now remove cap 23 at the distal end 22 ofhousing 20 and attach a needle 28, or other suitable device, viathreaded screw structure 27 (e.g., a luer lock) in distal end 22 ofhousing 20, as shown in FIG. 5F. FIG. 5F shows a mixing syringe whenmixed substances 78 are being been expelled from the device, which cancontinue until the distal end of plug seal 232 abuts the distal interiorend of the housing. Because of the engagement between connector 258 andconnection 268, proximal seal 260 and distal seal assembly 240 areconnected such that distal pressure against plunger rod 230 bydepressing 239 has displaced the two seals as a single seal unit asmixed substances 78 are expelled via needle assembly 28.

FIG. 6A to FIG. 6C show detailed views of the example embodiment ofdistal seal assembly 240 in the closed (FIG. 6A and FIG. 6C) and open(FIG. 6B) positions. In this embodiment, distal seal assembly 240comprises seal ring 242, which houses insert 250 which, in turn, housesplunger rod 230 and plug seal 232. Seal ring 242 includes exterior,radial circumferential ribs 243 that bear against the interior wall ofhousing 20, forming a substance-proof seal. Seal ring 242 furtherincludes internal annular steps 245, into which fit a radial flange 255extending outwardly from insert 250, such that the position of insert250 is fixed within seal ring 242 of distal seal assembly 240. Insert250 also includes connector 258, configured to mate with recess 268 ininsert 261 of proximal seal 260. The interior surfaces of insert 250form internal compartment 253, which allows limited axial movement ofplunger rod 230 and plug seal 232; and passage 254, which allowssubstance to flow when plug seal 232 is moved in the proximal positionwithin insert 250 (FIG. 6B). Regarding the movement of plunger 230, theinterior surfaces (i.e., the internal compartment) of insert 250 formdistal ledge 257 and proximal ledge 256, which stop movement of plungerrod 330 within insert 250 by abutting plunger rod flange 236, whichextends outwardly from plunger rod 230 at its junction with plug seal232. Between proximal ledge 256 and distal ledge 257, the interiorsurface of insert 250 forms channel 253 in which flange 236 can moveaxially. The interior surface of insert 250 also forms an inner wall252, which holds plug seal 232 in the closed position (FIG. 6A and FIG.6C) in which exterior annular ribs 235 of plug seal 232 bear againstinner wall 252 to form a substance-tight seal; and inner wall 252 thusdefines the distal opening 259 for fluid passage 244 (FIG. 6B) when plugseal 232 is proximally displaced within insert 250. Insert 250 comprisespassage 254, through which a substance cannot pass when opening 259 isblocked by plug seal 232 (FIG. 6A and FIG. 6C), but through which asubstance can pass when plug seal 232 is moved proximally and thus awayfrom opening 259 (FIG. 6B). In this particular embodiment, plunger rod230 connects to plug seal 232 via complementary threaded screw 231 (FIG.6C).

The embodiments described in FIG. 1 to FIG. 6 can further comprise aconnection aspect for connection to a needleless access device, such asan i.v. line or to a needle assembly. The connection aspect may bepre-formed as a distal portion of the syringe barrel housing.Alternatively, the syringe barrel may be a substantially straight barrelto which a connection adapter is mounted. An adapter mountable to asyringe barrel may have a luer connection portion and a barrel-engagingportion and a fluid aperture therethrough. The adapter facilitatesmounting a luer assembly to the barrel. The luer assembly may be a tipcap having a corresponding female luer fitment for connection to themale luer fitment of the luer connection portion of the adapter. Theluer assembly may alternatively be a luer needle assembly having aneedle body, cannula, and a needle tip having a corresponding femaleluer fitment for connection to the male luer fitment of the luerconnection portion of the adapter. The term male and female may be usedinterchangeably to describe corresponding components or aspects thereof.The adapter and syringe further comprise an immobile, compressibleneedle seal. The needle seal is adjacent to or engageable with thebarrel-engaging portion of the adapter. The needle seal sits within theinterior of the barrel or adapter, and has a fluid pass-through axiallylocated for the passage of fluid.

FIG. 7A to FIG. 7E are detailed views of another embodiment of a distalseal assembly and its components. In the embodiment shown in FIG. 7A,distal ring seal 342 comprises exterior rings 343 configured to bearagainst the inner wall of housing 20, and internal step 345 forreceiving exterior protrusions 355 that extend radially from insert 350(FIG. 7C). Plunger rod 330 extends axially in direction (D) throughinsert 350 and into inner lip formation 347 of elastomeric distal ringseal 342, forming a substance-proof, (e.g., fluid-tight) barrier.Plunger rod 330 may be smooth (FIG. 7D) or comprise circumferential ribs335 (FIG. 7E). Lip formation 347 is held on the side opposite of plungerrod 330 by inner wall 352 of insert 350. Plunger rod 330 is configuredwith at least a pair of distal indentations 334 positioned axially alonga distal portion of plunger rod 330 (FIG. 7D, 7E), which channels 334are inaccessible to substances when plunger rod 330 is positioned fullydistally within distal assembly 340 (FIG. 7A); but channels 334 areaccessible to substances when plunger rod 330 is positioned fullyproximally within distal seal assembly 340 (FIG. 7B, FIG. 8B).

As shown in FIG. 8A, plunger rod 330 may be configured withcomplementing screw/threads 338 or similar structures for securingplunger rod to a grip, such as pull 339 or a flanged button grip (seeFIG. 11, button 439). In this embodiment, plunger rod 330 furthercomprises a pair of radially extending protrusions 337 (see details inFIG. 7D and FIG. 7E), positioned within a groove or channel 351positioned longitudinally within insert 350 (FIG. 7C), which allowprotrusions 337 limited axial displacement of plunger rod 330 betweenthe distal stop 357 (valve in closed position, FIG. 7A, FIG. 8A) andproximal stop 356 (valve in open position, FIG. 7B, FIG. 8B) in channel351. Plunger rod 330 may also comprise annular rings 335 (FIG. 7E),configured to bear against the interior lip 347 of distal seal 342 toenhance the substance-proof seal. Insert 350 further comprises substancepassage 354, through which substances cannot flow when plunger rod 330is in the fully distal position within distal seal assembly 350 (FIG.7A), but which passages 354 allow fluid passage via the indentation 334in plunger 330 and the narrower distal end of plunger rod 330 whenplunger rod 330 has been moved proximally within insert 350 as definedby channel 351 (FIG. 7B). As further shown in FIG. 7B, when plunger rod330 has been moved axially until abutting proximal stop 356, insertsubstance passage 354 and an indentation in plunger rod 330 that formspassage 334 allow passage of substances through passage 344 in thedistal end of distal ring seal of distal assembly 340. Insert 350further comprises connector 358 for connecting with a complementaryrecess in the proximal seal (FIG. 8C and FIG. 8D).

It should be noted that the particular embodiment of the mixing syringedepicted in FIG. 8A to FIG. 8D relates to a prefilled mixing syringe. Inthese figures, proximal substance appears to be fluid and substance 70appears as solid particles. This is not a limitation or representationof particular substances, however, but merely a depiction of differentsubstances mixing. Indeed, either mutable chamber can hold solids orfluids as defined herein, and solids could dissolve completely andbecome liquids, so the intent of these figures is not to limit thesubstances that can be used in the mixing syringes. As shown in FIG. 8A,the mixing syringe includes a cap 23 in which internal barbs 23(a) helpsecure its position protecting the distal end of syringe housing 20.Housing 20 further include luer adapter 327, needle seal 329, grip 321,and cap 324 is inserted post-fill on the proximal end of the device.Housing 20 holds plunger rod 330, positioned axially therein andincluding screw/thread adaptation for connecting with pull 339. Mutableproximal chamber 73, holding substance 72, is defined by the positionsof proximal seal 360 and distal seal assembly 340. Mutable distalchamber 75, holding substance 70, is defined by the position of distalseal 342 and needle seal 329. Distal seal assembly 340 includes distalring seal 342, which holds insert 350 by the insert's radial shoulders355, and also engages with plunger rod 330. In this embodiment, plungerrod 330 includes a pair of radial protrusions 337 which are maintainedwithin insert 355 as shown in FIG. 7A and FIG. 7B. In FIG. 8A, as inFIG. 7A, the valve mechanism (the engagement of rod 330, insert 350 anddistal ring 342) is shown in the closed position. As shown in FIG. 8B,when the operator is ready to mix the contents of the prefilled syringe,proximal translation (pulling) of plunger rod 330 displaces plunger rod330 within insert 350 until protrusions 337 abut proximal edges ofchannels 351 (see FIG. 7B), opening fluid channels 354 and 344, andallowing proximal substance 72 to pass from shrinking mutable chamber 73and mix with distal substance 70 and form mixed substance 78 in growingmutable distal chamber 75.

As shown in FIG. 8C, maximal proximal translation of plunger rod 330brings distal ring seal 342 to meet with proximal seal 360, wherebyconnector 358 of insert 350 connects with connection 368 formed ininsert 361 held in proximal seal 360. Once proximal seal 360 and distalseal 342 are connected, distal pressure against plunger rod 330 pushesprotrusions 337 into the distal-most position within insert 350, whichcloses the valve mechanism. Mutable proximal and distal chambers are nowmerged and mixing is complete. The operator can attach needle assembly28 at this or a previous step. As shown in FIG. 8D, because distal andproximal seals are connected, distal pressure on rod 330 expels mixedsubstance 78 through needle assembly 28.

The embodiments described in FIG. 7 and FIG. 8 can further comprise aconnection aspect for connection to a needleless access device, such asan i.v. line or to a needle assembly, as described elsewhere herein.

In at least one embodiment, the mixing syringe includes accurate dosecontrol mechanisms, such as those described in WO 2013086167, althoughthe embodiment is not limited to any particular dose control device. Adose control mechanism allows for the accurate dosing and delivery ofmixed substances from a mixing syringe, in particular permitting theidentification and control of the dosage amount, the “priming” of thesyringe (i.e., evacuated of air bubbles) prior to administration ordelivery, and ensures the accurate delivery of microliter volumedosages, all within a device size that is similar to commonly usedconventional syringes available in the marketplace. The design the dosecontrol mechanism provides for mixing syringes that are safe and easy touse, and are aesthetically and economically appealing for users, withoutsignificantly altering technique currently employed by users to deliverinjectables. When utilized within a mixing syringe, the controlmechanism can be attached to the housing 20 after the mutable chambers75 and 85 have been filled with substances. This is often desired sothat the mixing syringe may be filled and assembled in standardpharmaceutical fill-finish process lines.

FIG. 9A to FIG. 9D presents an exemplary mixing syringe comprising adose control mechanism. The control mechanism includes control plunger614, a control housing 620, an adapter 618, and a screw 600. The controlplunger 614 includes a button 612 or similar structure as a unified orseparate component, but in any case the surface 612 provides a userinterface 612A with the device. In at least one embodiment, the controlhousing has a housing cover at its proximal end and a window to permitthe user to view the location of the control plunger within the housing.The control plunger may have one or more dose markings on the externalsurface of the plunger and the housing may have one or more guidemarkings with which to align plunger dose markings. Control housing 620may optionally include housing cover at its proximal end, for example,to close the interior of the housing 620 off from the environment or toaxially align plunger 614 within control housing 620. Control housing620 may further include a window 620A, which may be an opening (e.g., anaperture) in the housing or a transmissive, translucent or opticallymagnifying component. Control plunger 614 may include one or more dosemarkings on the external surface of the control plunger. Housing 620 mayhave one or more reference or guide markings, such as at the window620A, with which to align plunger dose markings.

The control mechanism includes control plunger 614 having coarse pitchscrew 614B on its exterior surface, with control housing 620 having acorresponding coarse pitch guide 620C along the interior surface of thehousing 620. Screw 600 has fine pitch screw 600B, which interfaces withfine pitch nut 618B of adapter 618, wherein the control plunger 614 hasan internal annular space 614C within which screw 600 at least partiallyresides. The control plunger 614, having the coarse pitch 614B (visiblein FIGS. 9A and 9C) is rotatable upon the corresponding coarse pitchguide 620C, and wherein at least a portion of the control plunger 614 isrotationally keyed to interface with a corresponding rotationally keyedportion of screw 600. The pitch on guide 620C is the same as pitch onplunger thread 614B. Similarly, screw 600 has a fine pitch thread 600Bwhich interfaces with a fine pitch nut 618B of adapter 618. The controlplunger 614 having the coarse pitch 614B is rotatable upon thecorresponding (e.g., “female”) coarse pitch guide 620C, which isrotationally keyed to the screw 600 having the fine pitch thread 600B.The terms “male” and “female” are intended to describe corresponding orcomplementary and interfacing threads or surfaces, and can be usedinterchangeably to describe corresponding aspects as would be readilyappreciated in the art. Screw 600 having fine pitch screw 600B engagesfemale fine pitch nut 618B of adapter 618. Upon use by the user, plungeraxially translates a first distance D1 causing screw to axiallytranslate a second distance D2, wherein D1 is always greater than D2 bya factor determined by the pitch ratio. Hence, rotation of controlplunger 614 results in axial translation of screw 600 and the resolutionof axial travel is dictated by pitch 600B.

Because the plunger 614 and screw 600 are rotationally keyed, eachhaving a respective screw pitch, rotational translation of the plunger614 rotates and axially translates the screw 600. The term “keyed” isused herein to mean any number of internal aspects which removably orslidably (in the axial sense) connect two or more components. Forexample, the control plunger 614 may be a hollow cylinder having acoarse pitch screw on at least some portion of the outer surface and aspline design along at least a portion of the inner surface. The splinedesign is configured to mate with, and transform or relay rotation to, acomplementary spline contained at a proximal end of the screw. Thisspline design element ensures that the plunger and screw arerotationally keyed. In the embodiment of FIG. 9, the spline orrotationally keyed aspect is at the proximal end 600C of screw 600, andwith its corresponding spline or rotationally keyed aspect in theannular space 614C of plunger 614. Many other shapes and configurationsmay be utilized to impart a rotationally “keyed” relationship betweenthese components, such that the first component may removably orslidably engage the second component in a manner that enables therotational keyed relationship and permits axial slip. Such componentsmay alternatively be keyed to have the shape of, for example, a cross orplus, a horizontal line or minus, a star, or a semi-circle shape, withthe corresponding component having the inverse of the shape on aninterior annular space. This arrangement or configuration allows the twocomponents, screw 600 and control plunger 614, to be rotationally keyedwhile allowing them to axially slip past each other. Both screw 600 andcontrol plunger 614 reside, at least partially or at some point ofoperation, within control housing 620.

Also visible in FIG. 9A is ledge 618C of adapter 618. Fine pitch nut618B (or simply “nut”), having the same fine pitch 600B of the screw600, may be used to brace the screw 600 and facilitate the transfer ofthe rotational movement of the plunger 614 into axial translation of thescrew 600. The pitch ratio of the coarse pitch to the fine pitchdictates the degree or resolution of axial travel of the screw 600,i.e., the distance that the screw 600 axially translates for eachrotation of control plunger 614. As a result, the user is provided withan ease of operation that enables them to accurately read and set thedosage amount. The pitch ratio can be set to enable “fine tuning” of thedosage amount, which is of particular importance for low-volume dosagequantities where variance may be significantly affected by plungertravel. A pitch ratio between coarse pitch screw 614B and fine pitchscrew 600B is from about 1:1 to about 20:1, for example fromapproximately 2:1 to approximately 10:1, or from about 4:1 to about 8:1.In a particular embodiment, the pitch ratio of coarse pitch screw 614Band fine pitch screw 600B is approximately 4:1.

The control mechanism may be attached, mounted, affixed, or otherwiseconnected at the proximal end of the barrel of housing 20, for examplevia adapter 618 and clip 619, such that at least a portion of the screw600 resides inside barrel 20. The portion of the control mechanismhoused within the standard barrel 20 may be contained in internal spacer617, which sits between and abuts the proximal side of proximal seal 360and the distal interior side of adapter 618. Screw 600 may be connectedto the proximal end of plunger rod 330, either directly or indirectly,to drive the axial translation of plunger rod 330 by a connectionaspect. Thus, for example, screw 600 may further include a screwconnection aspect which functions to connect the screw to the plungerrod. For example, distal end of screw 600 may be configured as ball 600Awhich fits in a socket 639 at the proximal end of plunger rod 330. Afurther component to a connection aspect, such as a plunger ring 602,may be utilized along screw 600, and proximal to socket 639, as part ofthe screw connection aspect to align or connect the components. Forexample, plunger ring 602 may be connected to screw 600. Additionally oralternatively, the connection between screw 600 and plunger rod 330 maybe a snap-fit connection, an interference-fit connection, or a number ofother connection methods known in the industry.

The connection between the screw 600 and plunger rod 330, when thesyringe is employed, is such that screw 600 is permitted to rotateaxially while plunger rod 330 and seal assemblies 360/340 remainrotationally fixed. Accordingly, as the control plunger 614 and screw600 of the control mechanism are axially rotated (e.g., by rotating dial616) and translated distally (e.g., to prime the needle or discharge themixed substance), the motion is relayed to the seal assemblies 360/340which are axially translated in tandem but not rotated.

For use, control plunger 614, screw 600 and plunger rod 330 aretranslated axially in the proximal direction to open the valve of distalseal assembly, and proximal axial translation continues until connector358 is engaged with proximal seal 360 such that mutable chambers 675 and685 have merged and substances are mixed 78, as shown in FIG. 7B. Thecontrol mechanism may then be utilized by the user to identify andselect drug dose for delivery. For example, in one embodiment a pitchratio between the coarse pitch and a fine pitch may be 4:1, such thatrotationally “screwing” or turning control plunger 614, via dial 616,axially translates the plunger component 614 four times as far as theaxial translation of the screw component 600. Accordingly, the user isprovided with a significant ease of operation because they may moreaccurately set the required dosage amount. Such a pitch ratio may be,for example, anywhere from the range of 1:1 to 20:1, as may be necessaryto obtain the required accuracy of the low-volume dosage amount. The“dialing-in” or “setting” may be facilitated by the dose markings on theplunger and guide markings on the housing.

The user may attach needle assembly 28, then axially rotate plunger 614via dial 616 or depress the button 612 to control the desired dosagevolume for delivery as shown in FIG. 9C. Axial rotation of the plunger614 causes coarse pitch screw 614B to travel within the correspondingcoarse pitch guide 620C of housing 620, which causes plunger 614 toaxially translate in the distal direction thereby reducing the dosagevolume within the drug chamber (i.e., by expelling excess volume).Because of the rotationally keyed interaction between plunger 614 andscrew 600 within the annular space 614C, rotation of the plunger 614causes screw 600 to axially rotate and translate. Because of the pitchratio between the plunger 614 and screw 600, each unit measure oftranslation in the distal direction of the plunger 614 results infractional (e.g., smaller, more resolved) translation of the screw 600in the distal direction. This has a number of benefits for accuratecontrol during delivery of low-volume doses. Primarily, the pitch ratiorelationship permits the user to accurately control the desired dose anddelivery of a drug treatment. Additionally, this pitch ratiorelationship allows the user to operate a syringe in a conventionalmanner, such as by depressing the plunger 614 a noticeable distance,while only resulting in fractional or small translation of screw 600 andplunger rod 330. Because of the function of the control mechanism andthe pitch ratio, any measure of distal translation of the plunger 614causes only an incremental measure of distal translation of the screw600 and plunger rod 330, permitting accurate dose delivery control bythe user. Axial translation of the screw 600 causes axial translation ofplunger rod 330 and seal assemblies 340/360. This axial motion in thedistal direction of the seal assemblies 340/360 force mixed substances78 out of barrel housing 20 through the needle assembly 28, as shown inFIG. 9D.

The embodiment described in FIG. 9 can further comprise a connectionaspect for connection to a needleless access device, such as an i.v.line or to a needle assembly. In this particular embodiment, the abilityto provide a universal adapter for connection to a narrow-gauge cannulais advantageous for the delivery of small dose volumes.

As noted, at least one embodiment provides for a mixing syringe in whichat least one of the chambers of mixing syringe may be filled just priorto use or at time of use, such as by the physician, pharmacist, nurse,caregiver, patient, end-user, or the like. The fill contents may includematerials having viscosity between about 0.25 cP and 2500 cP. Similarly,at least one of the chambers may be pre-filled, while one or more otherchambers are filled just prior to use or at time of use. Such anarrangement may be facilitated by the use of one or more lockingmechanisms, which enable the valve-type seal in the distal seal assemblyto remain closed during some stages of operation, but permit thevalve-type seal to open a fluid channel therethrough during other stagesof operation. This aspect allows for sequential injection from thedistal chamber of a distal substance (optionally more than once), thenfrom the proximal chamber of a proximal substance; or from the distalchamber of a distal substance (optionally more than once), then from themerged distal and proximal chambers of mixed substances.

FIG. 10A to FIG. 10C show an embodiment of a mixing syringe having alocking mechanism incorporated within the distal seal assembly as aconfiguration of insert 450. In this embodiment, plunger rod 430comprises a pair of protrusions 437 that extend radially from oppositesides of rod 430 and serve as locking pins that interface with lockinggroove 451(a) of insert 450 (integrated within the distal ring seal). Inthe locked configuration, shown in FIG. 10A, in which distal end 433 ofplunger rod 430 sits in the most-distal position (see also FIG. 11C),distal to insert hub 452, and blocks fluid passage, the distal chamberof the device can be emptied, or filled, or filled and emptied, thenrefilled, etc., independent of the contents of the proximal chamber.Once locking pins 437 are moved radially (in direction R), such as byrotation of plunger rod 430 out of locking groove 451(a) and intochannel 451 (as shown in FIG. 10B), the plunger rod can be moved axially(as shown by the arrow in FIG. 10C) from distal end 457 to proximal end456 of channel 451 (as shown in FIG. 10C); which exposes plunger rodindentation 434 and opens fluid passage 454 within the distal sealassembly, for fluid transfer of the proximal substance from the syringe,or for the mixing of distal and proximal substances. The axis androtation of the plunger rod in the unlocking motion are shown in thetransition from FIG. 10A to FIG. 10B.

Accordingly, in the first locked position, upon proximal translation ofthe plunger rod, the entire distal seal assembly moves proximally withinthe syringe barrel in a connected closed arrangement, such as foraspiration or filling of the distal chamber through the distal end ofthe syringe barrel (for example, for fill-at-time-of-use). In thisposition, the distal chamber can be filled and emptied (e.g., a dose canbe loaded and delivered) sequentially or repeatedly without mixing thedistal substance with the proximal substance. Once moved into the secondunlocked position the plunger rod may initially translate or move, suchas axially translate, thereby opening a fluid passage within the distalseal assembly. As the fluid channel is opened, fluid may pass throughthe fluid passage for mixing between the first chamber and the secondchamber and the plunger rod and distal seal assembly may be movedaxially in the proximal direction to enable complete mixing. At the endof the mixing stage, insert connector 458 enables connection of thedistal seal assembly to the proximal seal or a proximal seal insert,whereby both the proximal seal and distal seal assembly may betranslated axially as a connected, unitary component. Axial translationof plunger rod in the distal direction enables the mixed substance to bepushed out of the syringe, e.g., for delivery to the patient. Thelocking mechanism also provides a configuration for sequential injectionin which the distal substance is expelled, then the valve is opened andtranslated proximally to mate the distal seal assembly with the proximalseal, which moves the proximal substance into position to be expelled.In other words, sequential delivery of a distal substance followed by apreloaded proximal substance can be achieved without requiring themixing of substances.

According to the embodiment shown in FIG. 11A to FIG. 11G, the device isdesigned to enable an operator to draw a fluid (e.g., a pharmaceuticalliquid or diluent) into the syringe. In this embodiment, mixing syringehousing 20 comprises flange 21 engaged with snap cover 424; and includesmutable proximal chamber 73 prefilled with a diluent or liquid drug 72,and mutable distal chamber 475 into which a liquid drug or other fluid470 is drawn from an external container (e.g., vial, syringe, drug bagand the like). More specifically, FIG. 11A shows a mixing syringe “asshipped” in which the sterility and integrity of the distal end ofsyringe housing 22 is protected by cap 23. Distal end 22 is alsoconfigured with internal threading 27 for connection with a suitabledevice for loading and delivering fluid from the syringe. The proximalend of housing 20 also include grip 421. Housing 20 also includesmutable proximal chamber 72 that has been prefilled with liquidsubstance 73. Distal seal assembly 440 includes the components asdetailed in FIG. 10A to FIG. 10C, and the volume of proximal substance72, i.e., the size of mutable proximal chamber 73, is determined byplacement of distal seal assembly 440 and proximal seal 460 withinhousing 20. The drawing of liquid 470 into the syringe by proximaltranslation of plunger rod 430, achieved typically by pulling on plungerrod grip 439 (which is connected to plunger rod 430 via a screw/threadconnection 438), as shown in FIG. 11B, without causing fluid to betransferred to the proximal chamber 73 is enabled by a locking mechanism(i.e., engagement of plunger protrusions 437, which serve a locking pinswithin locking groove 451(a) in insert 450 in the distal seal assemblyas shown in FIG. 10A).

Moreover, the engagement of plunger rod 430 within distal seal assembly440 allows proximal chamber 73 to substantially maintain itspredetermined fill volume and pressure as it is displaced axially, alongwith proximal seal 460, within housing 20, despite the proximal movementof plunger rod 430. The amount of fluid 470 loaded into the syringe canbe exact or approximate; this can be predetermined by the user or bydesign. This embodiment also provides for optional sequential injection,at least once, from the distal chamber without mixing substances; or insequential order from mutable distal chamber then mutable proximalchamber. Once liquid 470 has been drawn into mutable chamber 475, byproximal displacement of plunger rod 430 as shown in FIG. 11B, theliquid 470 may be expelled or mixed with proximal substance 72. As shownin FIG. 11C, once distal substance 470 has been drawn into chamber 475,plunger rod 430 can be rotated radially within locking groove 451(a)into channel or groove 451 to unlock the valve mechanism (see FIG. 10B).Thereafter, continued proximal displacement of plunger rod 430 untilmotion is stopped by the interior proximal edge 456 of insert 450 (seeFIG. 10C), opening fluid passage 454 and 444 as shown in FIG. 11D.

Because of the engagement of plunger rod 430 with distal seal assembly440, further proximal displacement of plunger rod 430 causes proximalsubstance 72 to flow through fluid passages 434, 454 and 444, and mixwith distal substance 470 to form mixed substance 478, as mutableproximal chamber 73 shrinks and merges with the expanding mutable distalchamber 475. As shown in FIG. 11E, proximal displacement of distal sealassembly 440 ends with the meeting and connection with proximal seal460, in which connector 458 is received by complementary connection 468contained within insert 461 of proximal seal 460. At this stage, mixingis complete, and the mixed substances can be expelled. As shown in FIG.11F, distal pressure on plunger rod 430, typically by depressing grip439, pushes plunger rod 430 distally through insert 440 untilprotrusions 437 are stopped by distal end 457 of channel 451.Optionally, the operator may then radially rotate plunger rod 430 withininsert 450 until protrusions 437 abut the interior edge of lockinggroove 451(a) either before or as mixed substance is expelled fromdistal end of housing 22, as shown in FIG. 11F. Distal pressure onplunger rod 430 by depressing grip 439 ends once substance 478 has beenexpelled from housing when distal seal assembly abuts the inner distalwall of housing 20, as shown in FIG. 11G.

In another embodiment that provides for sequential injection, a lockingaspect that maintains the integrity of the mutable proximal chamber canbe configured in a proximal seal assembly. For example, FIG. 12A throughFIG. 12D show an embodiment comprising barrel 520 having proximal flange521, over which is affixed cap 524, typically connected to syringebarrel 520 after fill of at least a proximal substance. This embodimentfurther includes latch housing 580, which is secured by recess 585 towhich plunger rod flange 586 is held by screw/thread connection 538between plunger rod 530 and plunger button (grip) 539. A portion ofplunger rod 530 is further surrounded by seal rod 570, that is securedto the proximal seal by a radial collar 575 gripped within proximal sealinterior step 567. Seal rod 570 also includes connectors 578, configuredto engage release 581. More specifically, that in the locked position(FIG. 12A and FIG. 12C), release 581 fits into latch housing 580 througha slot, and includes an interior void through which, in the lockedposition, both the plunger rod and seal rod pass, but into whichconnector 578 is held in position by ledge 582 and the position ofrelease 581. This locking mechanism configured at the proximal side(surface not contacting the mixing substance) of the proximal seal,coordinates movement of the plunger rod and proximal seal, and becauseof the tight seal and vacuum forces of the prefilled proximal chamber,proximal translation of the plunger rod, by pulling grip 539, moves theproximal chamber and distal seal assembly in concert with the proximalchamber, and does not dislodge the closed-valve configuration of thedistal seal assembly. This configuration ensures concerted motionbetween the plunger rod and the distal seal assembly when a distalsubstance is drawn from an external vial/source. As shown in FIG. 12Band FIG. 12D, when the operator is ready to dispense substance from theproximal chamber, or mix the proximal substance with a distal substance,the operator presses interface 583 of release 581 into the slot of latchhousing 580, which dislodges ledge 582 from its abutment with rod sealconnector 578, freeing plunger rod 530 to move independently of seal rod570. When this locking feature is disabled, the device operates much thesame way as other embodiments described herein (i.e., withdrawing theplunger rod in the proximal direction opens the fluid path to allowmixing). It should be noted that this configuration of the proximallocking mechanism can be adapted for use with any of the distal sealassemblies or valves described herein, without limitation thereto.

Use of the locking mechanism described with reference to FIG. 12A toFIG. 12D is further illustrated with reference to the particular mixingsyringe illustrated in FIG. 13A to FIG. 13G. As shown in FIG. 13A, themixing syringe comprises barrel housing 20 having distal end 22 andinternal threads 27 that can be configured to accept a stopper, luerlock, luer lock adapter, needle assembly, or any suitable connection forcapping (as shipped), loading, and delivering the syringe contents (asused). FIG. 13A also shows that this embodiment includes mutableproximal chamber 73 preloaded with substance 72. Substance 72 can be apharmaceutically active or inactive fluid, adjuvant, diluent, etc., or amixture of these. The syringe is configured such that the mutable distalchamber can be loaded at or near the time of use. An example of suchtime-of-use loading is shown in FIG. 13B, in which it is evident thatproximal substance 72 in proximal chamber 73 has not been affected bythe loading is the distal substance 70 into mutable distal chamber 75.This feature is enabled by the configuration of seal rod 570, whichconnects proximal seal 560 to plunger rod 530 grip 539 via a latchhousing 580 and release 581, as detailed in FIG. 12A and FIG. 12B. Oncethe syringe components and proximal substance 72 are placed in thesyringe, the air-tight, fluid-tight seals formed by proximal seal 560and distal ring seal 542, the proximal translation of plunger rod 530 isdirectly translated via seal rod 570 and hub 575 held by step 567 totranslation of proximal seal 560, which indirectly causes the distalseal assembly 540 to move in concert in the proximal direction, therebyallowing filling of distal chamber 75 without displacing the valveclosure in distal seal assembly 540. Thereafter, the operator candispense distal substance 70 without mixing substances, which processcan be repeated as in FIG. 13A and FIG. 13B as the user requires.

Should the operator desire to mix substances, then distal substance 70can be drawn into mutable chamber 75 as described, or some portion canbe left in mutable distal chamber 75 from prior use, and the valve canbe opened. As shown in FIG. 13C, the user pushes interface 583 onrelease 581, moving it into the slot of latch housing 580, therebydisplacing seal rod shoulder 578 from resting place on edge 582, andthus disengaging seal rod 570 from plunger rod 530. As shown in FIG.13D, then plunger rod 530 is free to dislodge plunger distal end 533from the closed position in insert 550/distal seal 542 until protrusions537 abut their distal-most position within channel 551, in other wordsopen the valve and expose channel 534 for fluid passage 544, andproximal substance 72 can flow into distal chamber 75 and mix withsubstance 70 to form mixed substance 78. The distal seal assemblyillustrated in FIG. 13 is similar to that distal seal assembly 340detailed in FIG. 7, but this valve could have an alternate structuresuch as distal seal assembly 40, 140, 240 (as detailed in FIG. 6), oranother valve structure. As shown in FIG. 13E, further proximaltranslation of plunger rod 530 displaces proximal substance 72 andcollapses mutable proximal chamber 73, until such motion mates connector558 with recess 568 in insert 561 of proximal seal 560. Thereafter, asshown in FIG. 13F and FIG. 13G, depression of plunger rod 330 closes thevalve mechanism, and mixed substance 78 is expelled from the distal end522 of the mixing syringe.

Optionally, the operator can empty mutable distal chamber 75 (if it hadbeen filled, which is optional in this embodiment), disengage release581 by pressing 583, then pull on grip 539 to translate rod 530 and openfluid channels 534, 544 and 545 and collapse mutable proximal chamber73, thereby pushing substance 72 into the portion of the syringe distalto the distal seal (i.e., mutable distal chamber to the extent itexists). This method provides for sole or sequential dispensing ofsubstance 72 without mixing.

As can be seen from the FIG. 10 to FIG. 13 and the preceding discussion,the mixing syringes described herein can be used to dispense mixedsubstances 78 that have been mixed from prefilled mutable proximalchamber 73 and prefilled mutable distal chamber 75; dispense only distalsubstance 70; dispense only proximal substance 72 when distal chamber 75is not filled; dispense distal substance 70, then dispense proximalsubstance 72; dispense distal substance 70, then dispense mixedsubstance 78; dispense mixed substances 78 mixed from proximal substance72, prefilled proximal chamber 73 and fill-at-time-of-use distalsubstance 70; or practice any other variations of delivery as theconfigurations of the sequential mixing syringes allow.

The embodiments described in in FIG. 10 to FIG. 13 may also comprise aconnection aspect such as a luer adapter. The connection aspect may bepre-formed as a distal portion of the syringe barrel housing.Alternatively, the syringe barrel may be a substantially straight barrelto which a connection adapter is mounted. An adapter mountable to asyringe barrel may have a luer connection portion and a barrel-engagingportion and a fluid aperture therethrough. The adapter facilitatesmounting a luer assembly to the barrel. The luer assembly may be a tipcap having a corresponding female luer fitment for connection to themale luer fitment of the luer connection portion of the adapter. Theluer assembly may alternatively be a luer needle assembly having aneedle body, cannula, and a needle tip having a corresponding femaleluer fitment for connection to the male luer fitment of the luerconnection portion of the adapter. The term male and female may be usedinterchangeably to describe corresponding components or aspects thereof.The adapter and syringe further comprise an immobile, compressibleneedle seal. The needle seal is adjacent to or engageable with thebarrel-engaging portion of the adapter. The needle seal sits within theinterior of the barrel or adapter, and has a fluid pass-through axiallylocated for the passage of fluid

Further embodiments, which can also be used in a variety of methods asjust described, provide for mixing syringe devices in which the valvemechanism provides for repetitive mixing steps. An example of a valveembodiment for a repetitive mixing syringe is detailed in FIG. 14A toFIG. 14D. In this embodiment, plunger rod 730 comprises an indentation734, protrusion (locking pin) 737, and distal end 733. Insert 750comprises locking groove 751(a) which engages locking pin 737 on plungerrod 730. Insert 750 is held in position within distal seal 742 by hub752 and radial insert collar 755 which fits into distal seal interiorstep 745, and distal ring seal 742 is held within barrel 20 by annularribs 743. FIG. 14A shows plunger rod 730 locked in locking groove751(a). In this position, distal end 733 of plunger rod 730 blockspassage 744 in distal seal 742, and plunger rod indentation 734 abutsthe interior of insert 750 such that fluid passage between the proximaland distal mutable chambers is not possible (i.e., the valve is closed).Insert 750 further comprises channel 751 (not visible in cross section)which allows, when plunger rod 730 is rotated axially and pulledproximally, translation of plunger rod 730 into channel 791.

FIG. 14B shows plunger rod 730 in a proximal position within channel791, in which locking pin 737 is in the distal-most position in channel791, abutting proximal channel edge 796. Distal and proximal movement ofplunger rod 730 is regulated within channel 591 by protrusion 737 whichabuts the proximal edge of channel 791 at proximal edge 796, maintainingthe engagement of plunger rod 730 and distal seal 742 via insert 750. Inthe position shown in FIG. 14B, fluid passages 734, 744, and 754 areopen, allowing fluid communication between the distal and proximalchambers. FIG. 14C shows plunger rod 730 translated in the distaldirection within channel 791 until protrusion 737 abuts edge 797 on thedistal edge of channel 791. Plunger rod 730 remains engaged with distalseal 742, via insert 750, and distal seal 742. Moreover, plunger rod 730is not in the most-distal position within insert 750 (i.e., not inlocking groove 751(a)) so that fluid passages are not fully closed inthis position. Plunger rod 730 can move within channel 791 between stops796 and 797, as shown in FIG. 14B and FIG. 14C, until desired mixing isachieved, and translation of the distal seal in this open positionallows mixing of proximal and distal substances. This back-and-forthtranslation can continue until the distal seal assembly has moved to themost-proximal position, as shown in FIG. 14D, in which connector 758 ofinsert 750 has connected with recess 768 in proximal seal 760. In FIG.14D, plunger rod 730 abuts interior wall 762 of proximal seal 760, suchthat no fluid passes proximal seal 760, even though, as shown in FIG.14D, plunger rod protrusion 737 is in channel 791 and fluid passageremain in the open position. Plunger rod 730 can be translated distallyand radially such that protrusion 737 is returned to locking groove751(a) (as shown in FIG. 14A), such that distal end 733 of plunger rod730 is fully engaged and blocking fluid passage 744, but the proximaland distal seals remain connected for delivery of the mixed substance(see also FIG. 15F to FIG. 15H).

An embodiment of a repetitive mixing syringe is shown in FIG. 15A toFIG. 15H. The mixing syringe includes barrel housing 720 and cap 724that fits over barrel housing flange 721. In the view shown in FIG. 15A,mutable proximal chamber 773 is prefilled with proximal substance 72 andmutable distal chamber 775 is prefilled with distal substance 70; butthis device can also be used when mutable proximal chamber 773 isprefilled with proximal substance 72 and mutable distal chamber isfilled at or near time-of-use as described elsewhere herein. This ispossible because protrusion 737 serves as a locking pin in lockinggroove 751(a) such that distal seal 742 can be translated axiallywithout opening passage 744. As shown in FIG. 15B, plunger rod has beenmoved radially and distally (i.e., pulled and twisted) to the proximalmost edge 797 of channel 791. Distal and proximal movement of plungerrod 730 is regulated within channel 591 by locking pin 737 which abutsthe proximal edge of channel 791 at proximal edge 796, maintaining theengagement of plunger rod 730 and distal seal 742 via insert 750. Asshown in FIG. 15C, because plunger rod 730 remains engaged with distalseal 742, distal seal 742 is moved distally, causing displacement ofproximal substance 72 through passage 744. As shown in FIG. 15D,substances can be mixed further by depression of plunger rod 730 withinchannel 791, such that mixed substance or distal substance is forcedproximally through passages 744, 734 and 755. This motion between FIG.15B, FIG. 15C and FIG. 15D can be repeated as the operator desires. Theoperator may also use this motion when dispensing the substances (e.g.,into an i.v. or needle) for delivery of mixed substances in a gradientfrom most-distal to most-proximal mixed substances. As shown in FIG.15E, when the operator pulls plunger rod to the proximal-most position,distal seal 742 meets proximal seal 760 and insert connector 758connects with recess connection 768 of insert 761, connecting the distaland proximal seal assemblies. Thereafter, as shown in FIG. 15F, plungerrod 730 can be moved distally and radially (i.e., pushed and twisted)such that protrusion 737 locks back in locking groove 751(a) (see FIG.14A). As shown in FIG. 15G, subsequent distal axial displacement ofplunger rod 730, e.g., by pushing button 739 (attached to rod 730 viahub 738), expels mixed substance 778 through the distal end of housing722. As shown in FIG. 15H, delivery of mixed substance 78 is competewith the distal end of distal seal 742 abuts the interior distal end ofhousing 20.

In at least one embodiment, the mixing syringe further comprises aretractable needle assembly. An example barrel adapter for retractableneedle mechanism is described in WO 2013126118 or PCT/US2014/024781,PCT/US2014/040917, but the mixing syringes as described herein is notlimited to that particular configuration. The mixing syringes describedherein can be adapted to work with a variety of known retractable needlecomponents, and vice versa. By way of example, the needle safetymechanism may be a needle retraction safety mechanism as described in WO2006/119570, WO 2006/108243, WO 2009/003234, WO2011/075760,PCT/US2014/024781, PCT/US2014/040917, or U.S. Pat. No. 8,702,653,although without limitation thereto. In at least one embodiment of thepresent invention, the mixing syringe is also a needle retraction safetysyringe and incorporates the needle retraction safety mechanism asdisclosed in U.S. Pat. No. 8,702,653, PCT/US2014/024781, orPCT/US2014/040917.

An example embodiment of a mixing syringe further comprising a needleretraction mechanism is shown in FIG. 16A (“front view”) and FIG. 16B(“side view”). In the embodiment of FIG. 16A and FIG. 16B, the mixingsyringe comprises barrel 820, barrel cover 824 and cap 826 and fingerflange 825, which serves as a grip; and within which is axially disposedplunger rod 830 connected on its proximal end to button 839, which alsoserves as a grip. Plunger rod 830 is engaged with an insert housedwithin distal ring seal 842, through which the distal-most end 833 ofplunger rod 830 protrudes on the distal side, and insert connectors 858protrude on the proximal side. Insert connectors 858 are configured tomate with a complementary connection in proximal seal 860. The needleretraction mechanism comprises barrel tip 930A, through which needle 828is visible as the needle cap has been removed for these views. Needle828 is held in place by needle overmold assembly 922, a portion ofwhich, 922A, abuts a needle seal 916, which seal holds and centers theretractable needle mechanism at the proximal end of needle overmoldassembly 922. The distal portion of needle overmold 922 is centered andheld in the proximal end of barrel tip 930, in the interior of barrel820 at distal end 822. Needle overmold 922 is also engaged with snapbarrel 950, which is part of the actuator subassembly that permitsretraction of the needle. Briefly, snap barrel 950 comprises energizedbiasing members maintained in energized position by configuration ofbarrel tip 930 and an engagement of needle overmold assembly 922 andneedle seal 916. When mixed substances have been expelled through theneedle and the plunger rod presses distally on push bar 912, push bar912 deforms needle overmold assembly 922 from its position in needleseal 916 such that the proximal end of the actuation mechanism can nolonger hold the energized biasing members. As the biasing members springproximally within barrel, needle 828 is retracted proximally into thebarrel. The actuation mechanism can further include a capping orblocking feature that prevents the retracted needle from being exposed,thus protecting the operator and others from accidental needle sticks.In the configuration of FIG. 16, in which the actuation mechanism isinserted into or contiguous with the barrel of the mixing syringe, boththe mutable distal chamber and the mutable proximal chamber may beprefilled. Alternatively, a safety needle cartridge or similar deviceconfigured for attachment after loading and mixing can be attached via aluer connector, or similar means, to the mixing syringes describedherein.

Each of the devices, syringes, components, and methodologies describedherein may utilize additional known apparatus, or procedural steps, thatare known in the art. Throughout the specification, the aim has been todescribe the example embodiments of the invention without limiting theinvention to any one embodiment or specific collection of features.Various changes and modifications may be made to the embodimentsdescribed and illustrated without departing from the present invention.

1. A prefillable mixing syringe for administration of at least onesubstance comprising a syringe housing; a distal seal assembly axiallydisplaceably disposed within the housing, wherein the position of thedistal seal assembly defines a mutable distal chamber and a mutableproximal chamber within the housing; the distal seal assembly furthercomprising a valve that regulates a fluid passage between the proximaland distal chambers; a plunger rod positioned coaxially within thesyringe housing and engaged with the valve, wherein the plunger rodactuates the valve.
 2. The mixing syringe of claim 1, wherein thesyringe housing further comprises a proximal seal.
 3. The mixing syringeof claim 2, wherein at least one of the proximal seal and distal sealassembly comprises a connector configured to irreversibly connect thedistal and proximal seals.
 4. The mixing syringe of claim 1, wherein thesyringe further comprises an insert housed at least partially within thedistal seal assembly, wherein the insert comprises an internal cavityconfigured to engage the distal end of the plunger rod, and wherein theinsert comprises at least one fluid passage.
 5. The mixing syringe ofclaim 4, wherein the insert comprises at least one channel orcompartment that regulates movement of the plunger rod within theinsert.
 6. The mixing syringe of claim 4, wherein the insert comprises aconnector to irreversibly engage the proximal seal.
 7. The mixingsyringe of claim 1, wherein the plunger rod is configured to releasablyengage a locking mechanism to actuate the valve.
 8. The mixing syringeof claim 7, wherein the locking mechanism comprises a radial channelconfigured to be rotatably engaged by a plunger rod protrusion.
 9. Themixing syringe of claim 2, further comprising a releasable lockingmechanism comprising a connection for engaging the proximal seal and theplunger rod to prevent actuation of the valve, and further comprising arelease for disengaging the proximal seal from the plunger rod.
 10. Themixing syringe of claim 1, wherein the distal chamber, proximal chamber,or both, contains a substance.
 11. The mixing syringe of claim 10,wherein the substance comprises a pharmaceutical agent.
 12. The mixingsyringe of claim 11, wherein the pharmaceutical agent is selected fromthe group consisting of a biologic, a vaccine, a chemotherapeutic agent,a contrast agent, a small molecule, an immunogen, an antigen, aninterferon, a polyclonal antibody preparation, a monoclonal antibody, ananesthetic, an interfering RNA, a gene vector, an insulin, and acombination of any of these.
 13. The mixing syringe of claim 10, whereinthe substance is lyophilized.
 14. The mixing syringe of claim 10,wherein the substance comprises a diluent.
 15. The prefillable mixingsyringe of claim 1, wherein the syringe further comprises a dose controlmechanism.
 16. The prefillable mixing syringe of claim 1, wherein thesyringe further comprises a luer type connection at the distal end ofthe syringe housing.
 17. The prefillable mixing syringe of claim 1,wherein the syringe further comprises a retractable needle mechanism atthe distal end of the syringe housing.